Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib

Background-In comparing aspirin, nonselective nonsteroidal antiinflammatory agents (NSAIDs), and cyclooxygenase (COX)-2 inhibitors, variation in plate let inhibitory effects exists that may be associated with differential risk s of cardiovascular (CV) thrombotic events. Among the randomized, controlle d trials with the COX-2 inhibitor rofecoxib, one study demonstrated a signi ficant difference between rofecoxib and its NSAID comparator (naproxen) in the risk of CV thrombotic events. A combined analysis of individual patient data was undertaken to determine whether there was an excess of CV thrombo tic events in patients treated with rofecoxib compared with those treated w ith placebo or nonselective NSAIDs. Methods and Results-CV thrombotic events were assessed across 23 phase IIb to V rofecoxib studies. Comparisons were made between patients taking rofec oxib and those taking either placebo, naproxen (an NSAID with near-complete inhibition of platelet function throughout its dosing interval), or anothe r nonselective NSAIDs used in the development program (diclofenac, ibuprofe n, and nabumetone). The major outcome measure was the combined end point us ed by the Antiplatelet Trialists' Collaboration, which includes CV, hemorrh agic, and unknown deaths; nonfatal myocardial infarctions; and nonfatal str okes. More than 28 000 patients, representing > 14 000 patient-years at ris k, were analyzed. The relative risk for an end point was 0.84 (95% Cl: 0.51 , 1.38) when comparing rofecoxib with placebo;, 0.79 (95% CL 0.40, 1.55) wh en comparing rofecoxib with non-naproxen NSAIDs; and 1.69 (95% Cl: 1.07, 2. 69) when comparing rofecoxib with naproxen. Conclusions-This analysis provides no evidence for an excess of CV events f or rofecoxib relative to either placebo or the non-naproxen NSAIDs that wer e studied. Differences observed between rofecoxib and naproxen are likely t he result of the antiplatelet effects of the latter agent.